Modular organ-on-chip system with integrated 3D-printed channels

Abstract

Modular organ-on-chip system comprising: - a platform with external dimensions according to a microtiter plate standard, - a plurality of modular cell culture components for holding biological tissues, - wherein the platform and / or modules are manufactured by 3D printing from biocompatible material and can be fluidically connected to each other.

Description

[0001] Technical field: The present invention relates to a modular organ-on-a-chip system designed for high-throughput screening and personalized medicine applications. This innovative system utilizes advanced 3D printing technologies to create a flexible, modular platform capable of simulating complex biological environments with unprecedented accuracy and efficiency.

[0002] State of the art: The state of the art includes various organ-on-a-chip systems that utilize 3D printing technologies. These systems are designed to simulate biological environments to improve the efficiency of drug testing and personalized medicine applications. Examples of existing technologies can be found in scientific publications and patents, such as patent WO2013086502A1, which describes organ-on-a-chip devices manufactured by casting PDMS over 3D-printed molds, or EP2730645A3, which is neither modular nor compatible with commercially available high-throughput microplate readers. These systems suffer from the disadvantages of high complexity and a lack of standardization, which hinders their modular use in high-throughput analyses in common laboratories. Description of the invention: Problem underlying the invention

[0003] The invention is based on the objective of providing a modular organ-on-chip system that overcomes the disadvantages of the prior art and, in particular, enables a flexible, standardized and high-throughput compatible application.

[0004] The aim is to create a system consisting of several functional modules, each representing specific organ models (e.g., liver, heart, kidney), which can be fluidically interconnected within a common platform. This connection should allow metabolic products from one module to be directly transferred to a downstream module, thereby achieving a realistic simulation of interorganic interactions within an in vitro test system.

[0005] Furthermore, the system should be designed so that all modules can be operated without mechanical modification in a platform with standard dimensions according to the standards for microtiter plates and slides. This ensures compatibility with established high-throughput devices (e.g., automated microscopes or plate readers).

[0006] Furthermore, the platform is intended to enable flexible manufacturing using 3D printing, particularly for the rapid and application-specific production of diverse organ modules. The materials used must be biocompatible and suitable for microscopy, as well as allowing for the subsequent integration of additional functional elements, such as sensors or electronic components, without compromising the optical properties of the modules. Solution to the problem

[0007] The present invention solves the problem described above by providing a modular organ-on-a-chip system that is manufactured entirely from biocompatible or highly resistant materials using additive manufacturing technologies, in particular high-resolution 3D printing. Plant-based acrylate resins, glass-like polymers, high-temperature and solvent-resistant resins, ceramic materials, and ceramic-polymer hybrids are used as printing materials. Multi-component printing is also provided, allowing for the targeted combination of mechanical, optical, and functional properties within a single component.

[0008] The system consists of a modular platform with standardized external dimensions according to microtiter plate standards (e.g., ANSI / SLAS 1-2004), into which a variety of functional cell culture modules can be inserted. These modules can be fluidically connected to each other and to a microfluidic infrastructure integrated into the platform. The integrated channels within the platform are designed to ensure directed and controllable fluid distribution between the modules without requiring manual repositioning or rearrangement.

[0009] Furthermore, the system allows for the optional integration of sensor and / or electronic components into the modules or the platform structure itself. The interfaces provided for this purpose are designed to allow for subsequent installation or retrofitting without structural changes to the basic system. The sensors can be used, for example, for real-time monitoring of biological parameters such as pH value, oxygen saturation, or electrical impedance. Beneficial effects

[0010] The invention offers numerous technical and functional advantages over the prior art. The use of precise 3D printing technology enables high geometric accuracy while simultaneously allowing for complex channel structures and material combinations. This facilitates the reproducible production of both the platform and the functional cell culture modules with application-specific properties.

[0011] The system's modularity allows for flexible configuration of different organ models, with the modules connected within a common, controlled fluid circuit. Unlike known single-unit systems, this enables realistic simulation of interorganic interactions – for example, in the context of drug metabolism.

[0012] The standardized dimensions of the platform and modules ensure full compatibility with automated high-throughput instruments. This makes the platform particularly suitable for applications in personalized medicine, drug development, toxicology, and tissue physiology, where large numbers of samples need to be processed and analyzed quickly.

[0013] Furthermore, the optional integration of sensor components enables continuous monitoring of cell culture conditions, thereby significantly improving the quality, validity and efficiency of the experimental data. Example of implementation

[0014] In a preferred embodiment, the organ-on-a-chip system is manufactured entirely using digitally controlled 3D printing processes. Both the platform and the cell culture modules are produced from biocompatible, light- or heat-curing resins specifically selected for cell compatibility, optical transparency, and sterilizability. The printing process is performed at a resolution of ≤ 20 µm, enabling the precise creation of microfluidic channels with defined cross-sections and thin walls.

[0015] The platform has external dimensions according to the standard format of a microtiter plate (e.g. 127.76 × 85.48 mm). 2This allows for integration into existing laboratory automation systems. The platform features structured, internal microchannels that are connected to the cell culture modules via standardized interfaces. The modules themselves have a standardized geometry (e.g., 75 × 25 mm). 2 ) and can be precisely and securely fixed by means of a mechanical-magnetic holding mechanism.

[0016] To monitor relevant biological parameters, the modules can be equipped with sensors that, for example, record pH, temperature, or oxygen data in real time and transmit it to external evaluation units via an electrical interface. Alternatively, optical measurements can be performed directly through the transparent structure of the modules using confocal or fluorescence-based microscopy. Background and field of the invention

[0017] The present invention relates to a modular organ-on-a-chip system for patient-specific in vitro culture and analysis of biological tissues under controlled microfluidic conditions. The system is designed in particular for applications in personalized medicine, drug development, and toxicology. By combining standardized module sizes, a shared perfusion circuit, the ability to integrate patient biopsies and healthy organ models, and additive manufacturing (3D printing) from biocompatible materials, the system offers a versatile, scalable, and high-throughput-compatible platform. State of the art

[0018] The prior art includes organ-on-a-chip systems containing microfluidic components for simulating physiological microenvironmental conditions. WO2013086502A1 discloses a method for fabricating such systems using PDMS, which is carried out by casting over 3D-printed molds. EP2730645A3 describes an organ-on-a-chip system with simple microfluidic channels, but it is neither modular nor compatible with industrial high-throughput systems.

[0019] A key shortcoming of these existing systems lies in their lack of standardization and limited modularity. These limitations hinder the integration of patient-specific biopsy models into automated testing procedures and largely preclude the simultaneous investigation of organ interactions and side effects on healthy organs within the same system. Object of the invention

[0020] The object of the invention is to provide a standardized, modular, and highly functional organ-on-a-chip system that enables the cultivation of patient biopsies in combination with healthy organ models within a common or sequential fluid circuit. The system is intended for use in particular for the selection of individualized cancer therapies by directly mapping the effects and side effects of various therapeutic substances on tumor tissue as well as on patient-specific reference organ models.

[0021] Furthermore, the system should enable simple, cost-effective, and reproducible manufacturing through 3D printing with biocompatible materials and be compatible with high-throughput platforms. It should feature a modular structure, allowing for flexible configurations and expansion with sensor and electronic components. Solution to the task

[0022] The invention achieves the objective through a modular organ-on-a-chip system that has the following features: • A platform with external dimensions according to the microtiter plate standard (e.g. ANSI / SLAS 1-2004), equipped with integrated microfluidic channels for directed liquid distribution. • Several cell culture modules with a standardized shape (e.g. 25 × 75 mm) containing specific organ models or patient-specific tumor biopsies. • A fluidic connection between the modules and the platform, wherein the modules can be mechanically and / or magnetically fixed and detached. • Manufacturing all system components using 3D printing from biocompatible materials such as plant-based acrylate resins, ceramic composites or temperature-resistant plastics. • Optionally integrable interfaces for accommodating sensors (e.g. for pH, O2, tar) or electronic components. Beneficial effects

[0023] The system according to the invention enables, for the first time, the standardized integration of patient-specific tumor tissue into a high-throughput-compatible test environment, while simultaneously allowing healthy organs of the same patient to be considered in vitro. In this way, both therapeutic effects and systemic side effects can be simulated in a single test run.

[0024] Thanks to its modular architecture and material flexibility through 3D printing, the system can be easily adapted to different tissue types and experimental configurations. The standardized geometry allows for automated analysis using existing laboratory measurement technology (e.g., microscopy, plate readers).

[0025] The combination of tumor and organ models in a flow-through circuit allows for a realistic representation of pharmacodynamic and toxicological processes, thus representing a crucial advance for the preclinical evaluation of personalized treatment options. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] WO 2013086502A1 [0002, 0018] EP 2730645A3 [0002, 0018]

Claims

[1] Modular organ-on-a-chip system comprising: - a platform with external dimensions according to a microtiter plate standard, - a plurality of modular cell culture components for holding biological tissues, - wherein the platform and / or modules are manufactured by 3D printing from biocompatible material and can be fluidically connected to each other. [2] System according to claim 1, characterized by that the platform includes integrated microchannels which enable directed and controllable fluid distribution between the modules. [3] System according to one of the preceding claims, wherein the modules can be positioned and removed on the platform by mechanical and / or magnetic fixing elements. [4] System according to any of the preceding claims, wherein the platform and / or the modules consist of materials selected from the group consisting of plant-based acrylate resins, ceramic composites, high-temperature resistant or solvent-resistant synthetic resins. [5] System according to any one of the preceding claims, characterized by that sensors for real-time monitoring of biological parameters are integrated into the modules and / or the platform. [6] System according to one of the preceding claims, wherein the modules have standardized slide geometries (e.g. 25 × 75 mm) and are fully compatible with microscopy. [7] System according to one of the preceding claims, wherein the modules are manufactured using multi-component 3D printing to provide different material properties within a component. [8] System according to any of the preceding claims, wherein the platform is designed to operate multiple organ models of the same patient in a common or sequential perfusion circuit. [9] System according to any of the preceding claims, wherein at least one module contains a cell culture generated from a patient biopsy (e.g. tumor tissue) and at least one further module comprises a healthy organ model of the same patient, operated in the same or downstream perfusion stream to capture the effect and potential side effects of therapeutic substances in a patient-specific manner. [10] System according to any one of the preceding claims, characterized bythat the tumor module is generated by cultivating primary cells from a patient biopsy and the resulting tumor-on-a-chip unit serves to select a therapeutic regimen tailored to the patient while simultaneously recording possible systemic side effects.